PROJECT SUMMARY This administrative supplement is in response to NOT-AG-18-039 under active R01CA101795 (Novel Strategies for Intervention of Inflammatory Diseases and Cancer). Alzheimer?s disease (AD) is the most common form of dementia in the elderly. Development of AD is complex and involves interplay among central nervous system (CNS), innate immune signaling and microbiota, leading to neuroinflammation, amyloid-? deposition and tau aggregation. However, there is a huge knowledge gap between innate immune signaling/microbiota and AD. The key regulatory function of gut microbiota in AD development has been implicated in germ-free mice and patients treated with antibiotics or probiotics, but the precise mechanisms remain elusive. We found that some microbial taxa that significantly decreased in AD models (such as Lachnospiraceae and Bacteroidetes) were elevated in Tak1?M/?M mice compared with WT controls, and vice versa. We thus hypothesize that specific microbiota composition in Tak1?M/?M mice may ameliorate the AD pathogenesis in preclinical animal models. Furthermore, TAK1 signaling has been positively linked to inflammatory responses in CNS and AD development, and the depletion of Tak1 by Lyz2-Cre also leads to partial ablation of this gene in certain neurons and microglia. Our preliminary study also observed the increase of anti-inflammatory Th17 cells and cytokines (IL-17A, IL-22, and IL-10) in Tak1?M/?M mice. Importantly, the increase of IFN-? has been reported to ameliorate AD by decreasing the A? deposits. Therefore, we further hypothesize that these innate immune signaling and cytokines play critical roles in regulating the development of AD by controlling the inflammatory responses in CNS. To test our hypothesis, Aim 1.1 seeks to investigate the function of total microbiota components in Tak1?M/?M mice, as well as specific species/strains, in controlling AD pathogenesis; and Aim 1.2 will explore whether TAK1-mediated innate immune signaling, including key immune cells and cytokines, could regulate AD development. Upon successful completion of this one-year studies, we should have generated key preliminary data to apply for a R01 application to further investigate the link between microbiota, innate immune signaling and AD, and dissect the mechanisms by which microbiota and innate immune signaling regulate AD, thus allowing us to develop new approaches to the prevention and treatment of this disease.